Protective Immunity in Human Filariasis: A Role for Parasite-Specific IgA Responses
Identifieur interne : 000443 ( Istex/Corpus ); précédent : 000442; suivant : 000444Protective Immunity in Human Filariasis: A Role for Parasite-Specific IgA Responses
Auteurs : Bikash R. Sahu ; Madhu C. Mohanty ; Prakash K. Sahoo ; Ashok K. Satapathy ; Balachandran RavindranSource :
- The Journal of Infectious Diseases [ 0022-1899 ] ; 2008-08-01.
Abstract
Background. Filaria-specific antibodies of immunoglobulin (Ig) G, IgE, and IgM isotypes have been correlated with acquired immunity in the literature, but the status of filaria-specific IgA and its role in human filariasis has not been addressed. The present study attempts to fill this lacuna. Methods. Both total and filaria-specific IgA to different developmental stages of filarial parasites were quantified by solid-phase immunoassays in 412 clinically and parasitologically defined cases occurring in an area endemic for human bancroftian filariasis in Orissa, India. Results. Compared with other clinical categories, microfilariae carriers were deficient in total as well as filaria-specific IgA. More crucially, significantly high levels were observed in putatively immune control subjects from areas of endemicity. These associations were also related to sex; female subjects in each category displayed higher levels of filaria-specific IgA than did male subjects. Conclusion. The study demonstrates, for the first time, a positive correlation between protective immunity and increased levels of filaria-specific IgA in human bancroftian filariasis. Furthermore, filaria-specific IgA appears to be an immunological window for the sex-related differences in susceptibility to infection observed in human filariasis.
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DOI: 10.1086/589881
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<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title>Protective Immunity in Human Filariasis: A Role for Parasite-Specific IgA Responses</title><author><name sortKey="Sahu, Bikash R" sort="Sahu, Bikash R" uniqKey="Sahu B" first="Bikash R." last="Sahu">Bikash R. Sahu</name><affiliation><mods:affiliation>Regional Medical Research Centre, Bhubaneswar, India</mods:affiliation></affiliation></author><author><name sortKey="Mohanty, Madhu C" sort="Mohanty, Madhu C" uniqKey="Mohanty M" first="Madhu C." last="Mohanty">Madhu C. Mohanty</name><affiliation><mods:affiliation>Regional Medical Research Centre, Bhubaneswar, India</mods:affiliation></affiliation></author><author><name sortKey="Sahoo, Prakash K" sort="Sahoo, Prakash K" uniqKey="Sahoo P" first="Prakash K." last="Sahoo">Prakash K. Sahoo</name><affiliation><mods:affiliation>Regional Medical Research Centre, Bhubaneswar, India</mods:affiliation></affiliation></author><author><name sortKey="Satapathy, Ashok K" sort="Satapathy, Ashok K" uniqKey="Satapathy A" first="Ashok K." last="Satapathy">Ashok K. Satapathy</name><affiliation><mods:affiliation>Regional Medical Research Centre, Bhubaneswar, India</mods:affiliation></affiliation></author><author><name sortKey="Ravindran, Balachandran" sort="Ravindran, Balachandran" uniqKey="Ravindran B" first="Balachandran" last="Ravindran">Balachandran Ravindran</name><affiliation><mods:affiliation>Regional Medical Research Centre, Bhubaneswar, India</mods:affiliation></affiliation><affiliation><mods:affiliation>Institute of Life Sciences, Bhubaneswar, India</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: ravindran8@gmail.com</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:09A1CB0FBA6BC188AF0B11AB4C16287E69942032</idno><date when="2008" year="2008">2008</date><idno type="doi">10.1086/589881</idno><idno type="url">https://api.istex.fr/document/09A1CB0FBA6BC188AF0B11AB4C16287E69942032/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">000443</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">000443</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a">Protective Immunity in Human Filariasis: A Role for Parasite-Specific IgA Responses</title><author><name sortKey="Sahu, Bikash R" sort="Sahu, Bikash R" uniqKey="Sahu B" first="Bikash R." last="Sahu">Bikash R. Sahu</name><affiliation><mods:affiliation>Regional Medical Research Centre, Bhubaneswar, India</mods:affiliation></affiliation></author><author><name sortKey="Mohanty, Madhu C" sort="Mohanty, Madhu C" uniqKey="Mohanty M" first="Madhu C." last="Mohanty">Madhu C. Mohanty</name><affiliation><mods:affiliation>Regional Medical Research Centre, Bhubaneswar, India</mods:affiliation></affiliation></author><author><name sortKey="Sahoo, Prakash K" sort="Sahoo, Prakash K" uniqKey="Sahoo P" first="Prakash K." last="Sahoo">Prakash K. Sahoo</name><affiliation><mods:affiliation>Regional Medical Research Centre, Bhubaneswar, India</mods:affiliation></affiliation></author><author><name sortKey="Satapathy, Ashok K" sort="Satapathy, Ashok K" uniqKey="Satapathy A" first="Ashok K." last="Satapathy">Ashok K. Satapathy</name><affiliation><mods:affiliation>Regional Medical Research Centre, Bhubaneswar, India</mods:affiliation></affiliation></author><author><name sortKey="Ravindran, Balachandran" sort="Ravindran, Balachandran" uniqKey="Ravindran B" first="Balachandran" last="Ravindran">Balachandran Ravindran</name><affiliation><mods:affiliation>Regional Medical Research Centre, Bhubaneswar, India</mods:affiliation></affiliation><affiliation><mods:affiliation>Institute of Life Sciences, Bhubaneswar, India</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: ravindran8@gmail.com</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">The Journal of Infectious Diseases</title><title level="j" type="abbrev">The Journal of Infectious Diseases</title><idno type="ISSN">0022-1899</idno><idno type="eISSN">1537-6613</idno><imprint><publisher>The University of Chicago Press</publisher><date type="published" when="2008-08-01">2008-08-01</date><biblScope unit="volume">198</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="434">434</biblScope><biblScope unit="page" to="443">443</biblScope></imprint><idno type="ISSN">0022-1899</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0022-1899</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">Background. Filaria-specific antibodies of immunoglobulin (Ig) G, IgE, and IgM isotypes have been correlated with acquired immunity in the literature, but the status of filaria-specific IgA and its role in human filariasis has not been addressed. The present study attempts to fill this lacuna. Methods. Both total and filaria-specific IgA to different developmental stages of filarial parasites were quantified by solid-phase immunoassays in 412 clinically and parasitologically defined cases occurring in an area endemic for human bancroftian filariasis in Orissa, India. Results. Compared with other clinical categories, microfilariae carriers were deficient in total as well as filaria-specific IgA. More crucially, significantly high levels were observed in putatively immune control subjects from areas of endemicity. These associations were also related to sex; female subjects in each category displayed higher levels of filaria-specific IgA than did male subjects. Conclusion. The study demonstrates, for the first time, a positive correlation between protective immunity and increased levels of filaria-specific IgA in human bancroftian filariasis. Furthermore, filaria-specific IgA appears to be an immunological window for the sex-related differences in susceptibility to infection observed in human filariasis.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Bikash R. Sahu</name><affiliations><json:string>Regional Medical Research Centre, Bhubaneswar, India</json:string></affiliations></json:item><json:item><name>Madhu C. Mohanty</name><affiliations><json:string>Regional Medical Research Centre, Bhubaneswar, India</json:string></affiliations></json:item><json:item><name>Prakash K. Sahoo</name><affiliations><json:string>Regional Medical Research Centre, Bhubaneswar, India</json:string></affiliations></json:item><json:item><name>Ashok K. Satapathy</name><affiliations><json:string>Regional Medical Research Centre, Bhubaneswar, India</json:string></affiliations></json:item><json:item><name>Balachandran Ravindran</name><affiliations><json:string>Regional Medical Research Centre, Bhubaneswar, India</json:string><json:string>Institute of Life Sciences, Bhubaneswar, India</json:string><json:string>E-mail: ravindran8@gmail.com</json:string></affiliations></json:item></author><language><json:string>unknown</json:string></language><originalGenre><json:string>research-article</json:string></originalGenre><abstract>Background. Filaria-specific antibodies of immunoglobulin (Ig) G, IgE, and IgM isotypes have been correlated with acquired immunity in the literature, but the status of filaria-specific IgA and its role in human filariasis has not been addressed. The present study attempts to fill this lacuna. Methods. Both total and filaria-specific IgA to different developmental stages of filarial parasites were quantified by solid-phase immunoassays in 412 clinically and parasitologically defined cases occurring in an area endemic for human bancroftian filariasis in Orissa, India. Results. Compared with other clinical categories, microfilariae carriers were deficient in total as well as filaria-specific IgA. More crucially, significantly high levels were observed in putatively immune control subjects from areas of endemicity. These associations were also related to sex; female subjects in each category displayed higher levels of filaria-specific IgA than did male subjects. Conclusion. The study demonstrates, for the first time, a positive correlation between protective immunity and increased levels of filaria-specific IgA in human bancroftian filariasis. Furthermore, filaria-specific IgA appears to be an immunological window for the sex-related differences in susceptibility to infection observed in human filariasis.</abstract><qualityIndicators><score>9.172</score><pdfWordCount>5658</pdfWordCount><pdfCharCount>34635</pdfCharCount><pdfVersion>1.3</pdfVersion><pdfPageCount>10</pdfPageCount><pdfPageSize>594 x 783 pts</pdfPageSize><refBibsNative>true</refBibsNative><abstractWordCount>181</abstractWordCount><abstractCharCount>1323</abstractCharCount><keywordCount>0</keywordCount></qualityIndicators><title>Protective Immunity in Human Filariasis: A Role for Parasite-Specific IgA Responses</title><genre><json:string>research-article</json:string></genre><host><title>The Journal of Infectious 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Responses</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>The University of Chicago Press</publisher><availability><p>© 2008 by the Infectious Diseases Society of America</p></availability><date>2008</date></publicationStmt><notesStmt><note>Present affiliations: Institute of Life Sciences, Bhubaneswar (B.R.S.), and Enterovirus Research Centre, Mumbai (M.C.M.), India.</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">Protective Immunity in Human Filariasis: A Role for Parasite-Specific IgA Responses</title><author xml:id="author-0000"><persName><forename type="first">Bikash R.</forename><surname>Sahu</surname></persName><note type="biography">a Present affiliations: Institute of Life Sciences, Bhubaneswar (B.R.S.), and Enterovirus Research Centre, Mumbai (M.C.M.), India.</note><affiliation>a Present affiliations: Institute of Life Sciences, Bhubaneswar (B.R.S.), and Enterovirus Research Centre, Mumbai (M.C.M.), India.</affiliation><affiliation>Regional Medical Research Centre, Bhubaneswar, India</affiliation></author><author xml:id="author-0001"><persName><forename type="first">Madhu C.</forename><surname>Mohanty</surname></persName><note type="biography">a Present affiliations: Institute of Life Sciences, Bhubaneswar (B.R.S.), and Enterovirus Research Centre, Mumbai (M.C.M.), India.</note><affiliation>a Present affiliations: Institute of Life Sciences, Bhubaneswar (B.R.S.), and Enterovirus Research Centre, Mumbai (M.C.M.), India.</affiliation><affiliation>Regional Medical Research Centre, Bhubaneswar, India</affiliation></author><author xml:id="author-0002"><persName><forename type="first">Prakash K.</forename><surname>Sahoo</surname></persName><affiliation>Regional Medical Research Centre, Bhubaneswar, India</affiliation></author><author xml:id="author-0003"><persName><forename type="first">Ashok K.</forename><surname>Satapathy</surname></persName><affiliation>Regional Medical Research Centre, Bhubaneswar, India</affiliation></author><author xml:id="author-0004" corresp="yes"><persName><forename type="first">Balachandran</forename><surname>Ravindran</surname></persName><email>ravindran8@gmail.com</email><affiliation>Regional Medical Research Centre, Bhubaneswar, India</affiliation><affiliation>Institute of Life Sciences, Bhubaneswar, India</affiliation></author><idno type="istex">09A1CB0FBA6BC188AF0B11AB4C16287E69942032</idno><idno type="DOI">10.1086/589881</idno></analytic><monogr><title level="j">The Journal of Infectious Diseases</title><title level="j" type="abbrev">The Journal of Infectious Diseases</title><idno type="pISSN">0022-1899</idno><idno type="eISSN">1537-6613</idno><idno type="PublisherID">jid</idno><idno type="PublisherID-hwp">jinfdis</idno><imprint><publisher>The University of Chicago Press</publisher><date type="published" when="2008-08-01"></date><biblScope unit="volume">198</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="434">434</biblScope><biblScope unit="page" to="443">443</biblScope></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2008</date></creation><abstract><p>Background. Filaria-specific antibodies of immunoglobulin (Ig) G, IgE, and IgM isotypes have been correlated with acquired immunity in the literature, but the status of filaria-specific IgA and its role in human filariasis has not been addressed. The present study attempts to fill this lacuna. Methods. Both total and filaria-specific IgA to different developmental stages of filarial parasites were quantified by solid-phase immunoassays in 412 clinically and parasitologically defined cases occurring in an area endemic for human bancroftian filariasis in Orissa, India. Results. Compared with other clinical categories, microfilariae carriers were deficient in total as well as filaria-specific IgA. More crucially, significantly high levels were observed in putatively immune control subjects from areas of endemicity. These associations were also related to sex; female subjects in each category displayed higher levels of filaria-specific IgA than did male subjects. Conclusion. The study demonstrates, for the first time, a positive correlation between protective immunity and increased levels of filaria-specific IgA in human bancroftian filariasis. Furthermore, filaria-specific IgA appears to be an immunological window for the sex-related differences in susceptibility to infection observed in human filariasis.</p></abstract></profileDesc><revisionDesc><change when="2008-08-01">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/document/09A1CB0FBA6BC188AF0B11AB4C16287E69942032/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup, element #text not found" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="research-article">
<front>
<journal-meta>
<journal-id journal-id-type="hwp">jinfdis</journal-id>
<journal-id journal-id-type="publisher-id">jid</journal-id>
<journal-title>The Journal of Infectious Diseases</journal-title>
<abbrev-journal-title>The Journal of Infectious Diseases</abbrev-journal-title>
<issn pub-type="ppub">0022-1899</issn>
<issn pub-type="epub">1537-6613</issn>
<publisher>
<publisher-name>The University of Chicago Press</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.1086/589881</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Major Articles and Brief Reports</subject>
<subj-group subj-group-type="heading">
<subject>Parasites</subject>
<subj-group subj-group-type="heading">
<subject>Major Articles</subject>
</subj-group>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>Protective Immunity in Human Filariasis: A Role for Parasite-Specific IgA Responses</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name><surname>Sahu</surname><given-names>Bikash R.</given-names></name>
<xref ref-type="aff" rid="AU1"><sup>1</sup></xref>
<xref ref-type="fn" rid="FN1"><sup>a</sup></xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Mohanty</surname><given-names>Madhu C.</given-names></name>
<xref ref-type="aff" rid="AU1"><sup>1</sup></xref>
<xref ref-type="fn" rid="FN1"><sup>a</sup></xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Sahoo</surname><given-names>Prakash K.</given-names></name>
<xref ref-type="aff" rid="AU1"><sup>1</sup></xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Satapathy</surname><given-names>Ashok K.</given-names></name>
<xref ref-type="aff" rid="AU1"><sup>1</sup></xref>
</contrib>
<contrib contrib-type="author" corresp="yes">
<name><surname>Ravindran</surname><given-names>Balachandran</given-names></name>
<xref ref-type="aff" rid="AU1"><sup>1</sup></xref>
<xref ref-type="aff" rid="AU2"><sup>2</sup></xref>
<xref ref-type="corresp" rid="COR1"></xref>
</contrib>
<aff id="AU1"><label>1</label><institution>Regional Medical Research Centre</institution>, <addr-line>Bhubaneswar, India</addr-line></aff>
<aff id="AU2"><label>2</label><institution>Institute of Life Sciences</institution>, <addr-line>Bhubaneswar, India</addr-line></aff>
</contrib-group>
<author-notes>
<fn fn-type="current-aff" id="FN1">
<label>a</label>
<p>Present affiliations: Institute of Life Sciences, Bhubaneswar (B.R.S.), and Enterovirus Research Centre, Mumbai (M.C.M.), India.</p>
</fn>
<corresp id="COR1">Reprints or correspondence: Dr. Balachandran Ravindran, Director, Institute of Life Sciences, Nalco Square, Bhubaneswar, Orissa, 751023, India (<email>ravindran8@gmail.com</email>; <email>balaravi@ils.res.in</email>).</corresp>
</author-notes>
<pub-date pub-type="ppub">
<day>1</day>
<month>8</month>
<year>2008</year>
</pub-date>
<volume>198</volume>
<issue>3</issue>
<fpage>434</fpage>
<lpage>443</lpage>
<history>
<date date-type="received">
<day>21</day>
<month>10</month>
<year>2007</year>
</date>
<date date-type="accepted">
<day>19</day>
<month>2</month>
<year>2008</year>
</date>
</history>
<copyright-statement>© 2008 by the Infectious Diseases Society of America</copyright-statement>
<copyright-year>2008</copyright-year>
<abstract>
<p><bold><italic>Background.</italic></bold> Filaria-specific antibodies of immunoglobulin (Ig) G, IgE, and IgM isotypes have been correlated with acquired immunity in the literature, but the status of filaria-specific IgA and its role in human filariasis has not been addressed. The present study attempts to fill this lacuna.</p>
<p><bold><italic>Methods.</italic></bold> Both total and filaria-specific IgA to different developmental stages of filarial parasites were quantified by solid-phase immunoassays in 412 clinically and parasitologically defined cases occurring in an area endemic for human bancroftian filariasis in Orissa, India.</p>
<p><bold><italic>Results.</italic></bold> Compared with other clinical categories, microfilariae carriers were deficient in total as well as filaria-specific IgA. More crucially, significantly high levels were observed in putatively immune control subjects from areas of endemicity. These associations were also related to sex; female subjects in each category displayed higher levels of filaria-specific IgA than did male subjects.</p>
<p><bold><italic>Conclusion.</italic></bold> The study demonstrates, for the first time, a positive correlation between protective immunity and increased levels of filaria-specific IgA in human bancroftian filariasis. Furthermore, filaria-specific IgA appears to be an immunological window for the sex-related differences in susceptibility to infection observed in human filariasis.</p>
</abstract>
</article-meta>
</front>
<body>
<p>Lymphatic filariasis, a chronic and debilitating tropical disease that often leads to clinical manifestations (such as lymphedema, elephantiasis, and/or hydrocele), is caused by vectorborne nematode parasites (e.g., <italic>Wuchereria bancrofti, Brugia malayi</italic>, and <italic>Brugia timori</italic>) [<xref ref-type="bibr" rid="R1">1</xref>]. In the absence of any preventive vaccine and effective chemotherapy to kill lymphatic-dwelling adult-stage parasites (which persist in infected hosts for several years), ∼120 million people suffer from at least one form of the disease, and ∼1.3 billion are at risk of infection [<xref ref-type="bibr" rid="R2">2</xref>].</p>
<p>The existence of acquired immunity in human filariasis has been a subject of intense debate, because the nature of protective immunity, if any, is yet to be unambiguously demonstrated [<xref ref-type="bibr" rid="R3">3</xref>]. Antibody and T cell responses in human filarial infections have been analyzed with a view to understanding their relevance to the development of protective immunity [<xref ref-type="bibr" rid="R4">4</xref>]. The role played by filaria-specific antibodies in preventing the persistence of infection or the development of chronic disease manifestations in lymphatic filariasis is still not understood. Early work in this area focused on antibody responses in microfilaremic individuals compared with subjects with chronic lymphatic pathology or subjects from areas of endemicity who have been exposed to infective bites but do not display any patent infection (hereafter, “endemic controls”), and findings suggested qualitative and quantitative differences in the production of filaria-specific antibody responses [<xref ref-type="bibr" rid="R5">5</xref>–<xref ref-type="bibr" rid="R7">7</xref>]. Individuals with active filarial infection display higher levels of filaria-specific IgG4 but lower levels of IgG3 and IgE than do subjects free of established infection, and raised levels of filaria-specific IgG1 and IgG2 have been correlated with the presence of microfilariae (Mf), irrespective of the presence or absence of adult worms [<xref ref-type="bibr" rid="R8">8</xref>]. Negative associations have been reported between (1) IgG1, IgG2, and IgE antibodies and Mf status and (2) IgG3 and filarial antigenemia, and positive correlations between IgG4 levels and active filarial infection have also been reported [<xref ref-type="bibr" rid="R9">9</xref>]. These and other investigators have quantified the status of IgG, IgM, and IgE responses to different filarial antigens, but, curiously, there have been no reports in the literature on the status of IgA responses in human bancroftian filariasis. Investigations of other helminthic infections, such as infections with <italic>Schistosoma mansoni, Taenia taeniformis</italic>, and <italic>Trichinella spiralis</italic>, have indicated a protective role for parasite-specific IgA [<xref ref-type="bibr" rid="R10">10</xref>–<xref ref-type="bibr" rid="R12">12</xref>], and a negative correlation has been observed between parasite-specific IgA levels and egg counts in subjects with <italic>Schistosoma</italic> infections, indicating a role for IgA in restricting the intensity of infections [<xref ref-type="bibr" rid="R13">13</xref>]. In this communication, we report the results of our investigations into the role played by IgA antibodies in human bancroftian filariasis. We considered the absence of demonstrable patent infection and disease manifestations as indicators of protective immunity. We report for the first time a protective role for IgA antibodies in human filariasis: putatively immune endemic control subjects free of filarial infection and/or disease displayed significantly higher levels of filaria-specific antibodies of the isotype IgA, and, conversely, infected subjects with circulating Mf displayed significantly lower levels of IgA antibodies than did other clinical groups.</p>
<sec sec-type="subjects|materials|methods">
<title>Subjects, Materials, and Methods</title>
<p><bold><italic>Parasites.</italic></bold> Male and female adult filarial parasites <italic>(Setaria digitata)</italic> were collected from the peritonea of slaughtered cattle and added to sterile Hank's balanced salt solution containing antibiotics [<xref ref-type="bibr" rid="R14">14</xref>]. Lyophilized third-stage larvae and adult worms of <italic>Brugia pahangi</italic> were gifts from E. Devaney, University of Glasgow.</p>
<p><bold><italic>Collection of human blood samples for serum.</italic></bold> Blood samples were drawn from endemic subjects in the state of Orissa, India. Clinical examination and nocturnal blood survey were conducted in 6 villages in Orissa: Rathipur, Ranapur, Siruli, Beldal, Beleswarpatna, and Bhimpur. The individuals were examined clinically for the presentation of acute or/and chronic disease manifestations of lymphatic filariasis by means of a proforma. The criteria for inclusion or exclusion and for precise classification of clinical groups—namely, subjects with chronic filarial disease, Mf carriers, subjects with cryptic infections, and endemic controls—have been elaborately described by us elsewhere [<xref ref-type="bibr" rid="R15">15</xref>]. Approximately 5 mL of blood was collected from person in each of the above categories, but only from those who volunteered to give blood samples. Serum samples were separated and frozen at −20°C. Approval for the study was obtained from the institutional ethical committee of the Regional Medical Research Center (Indian Council of Medical Research), Bhubaneswar, Orissa, and informed consent was given by the study subjects for the collection of blood samples. Serum samples from blood bank donors residing in filaria-nonendemic areas were gifts from A. Hoerauf, Bonn University.</p>
<p><bold><italic>Preparation of soluble filarial antigens.</italic></bold> PBS-solubilized extracts from adult-stage <italic>S. digitata</italic> parasites (male and female worms separately) and soluble extract of embryogenic stages of female adult <italic>S. digitata</italic> were prepared as described by us elsewhere [<xref ref-type="bibr" rid="R14">14</xref>], and the antigens were designated as <italic>Sd</italic>-M-Ag, <italic>Sd</italic>-F-Ag, and <italic>Sd</italic>-IUS-Ag for this study. Similarly, extracts of adult <italic>B. pahangi</italic> worms were prepared and labeled as <italic>Bp</italic>-F-Ag. Protein and carbohydrate fractions of <italic>Sd</italic>-F-Ag were prepared as described elsewhere [<xref ref-type="bibr" rid="R16">16</xref>]. For preparation of L3 extracts of <italic>B. pahangi</italic>, lyophilized larvae were ultrasonicated in PBS and labeled as <italic>Bp</italic>-L3-Ag. All of the solubilized antigen preparations were frozen at −20°C until further use.</p>
<p><bold><italic>Preparation of excretory-secretory antigen of female</italic> S. digitata.</bold> Excretory-secretory antigens from adult female <italic>S. digitata</italic> worms were prepared by a procedure described by us elsewhere [<xref ref-type="bibr" rid="R14">14</xref>]. The product was labeled <italic>Sd</italic>-F-ES-Ag and was stored at −20°C until further use.</p>
<p><bold><italic>Carbohydrate and protein estimation.</italic></bold> The protein content in all parasite antigen preparations was estimated using Folin-Ciocalteu's phenol reagent, and the carbohydrate content was quantified using phenol sulfuric acid reagent, as described elsewhere [<xref ref-type="bibr" rid="R17">17</xref>].</p>
<p><bold>W. bancrofti <italic>antigen assay (Og<sub>4</sub>C<sub>3</sub>).</italic></bold> Circulating filarial antigen (CFA) levels in serum samples were measured as described by us elsewhere [<xref ref-type="bibr" rid="R15">15</xref>], using a TropBio ELISA Kit (Tropical Biotechnology) according to the manufacturer's protocol. Levels are expressed as arbitrary antigen units, determined according to internal standards provided in the kit.</p>
<p><bold><italic>ELISA.</italic></bold> A lectin-based method was used to quantify total IgA1 in serum samples, as described elsewhere [<xref ref-type="bibr" rid="R18">18</xref>]. First, 96-well polystyrene plates (MaxiSorp; Nunc) were coated with Jacalin lectin <italic>(Artocarpus integrifolia)</italic> (L-3515; Sigma) at a concentration of 10 µg/well in 0.15 mol/L carbonate buffer (pH 9.6). After wells were blocked with 1% skim milk in PBS, 200-fold-diluted human filarial serum was incubated in PBS with 0.1% skim milk and Tween 20. Bound IgA was detected by using 1000-fold-diluted peroxidase-labeled anti-human IgA (P0216; Dako) in the same buffer. The enzyme activity was measured using orthophenylenediamine (P1526; Sigma). Absorbance was read at 492 nm, and the results are expressed as arbitrary ELISA units, determined using internal laboratory standard serum. Levels of IgA to different filarial extracts in human filarial serum samples were quantified by the method described above, with the following modifications. Plates were coated with 1 µg/well <italic>Sd</italic>-F-Ag, <italic>Sd</italic>-M-Ag, <italic>Bp</italic>-F-Ag, <italic>Sd</italic>-F-ES-Ag, <italic>Sd</italic>-F-pro (protein), <italic>Sd</italic>-IUS-Ag, or <italic>Bp</italic>-L3-Ag in PBS. Before being coated with <italic>Sd</italic>-F-cho (carbohydrate), plates were pretreated with poly-<sc>l</sc>-lysine hydrochloride (P1274; Sigma), as described by us elsewhere [<xref ref-type="bibr" rid="R16">16</xref>]. First, human filarial serum was diluted serially in PBS-Tween with 0.1% skim milk (25–25,600-fold dilutions) and were tested for levels of filaria-specific IgA to <italic>Sd</italic>-F-Ag. A serum dilution of 1:100 was considered optimum for quantifying serum IgA.</p>
<p><bold><italic>Immunoperoxidase assay.</italic></bold> We used an immunoperoxidase assay to detect IgA to the surface (epicuticle or cuticle) of adult female worms, as described by us elsewhere for anti-sheath antibodies [<xref ref-type="bibr" rid="R14">14</xref>], with the following modifications. Human serum, diluted 10-fold in PBS containing 0.1% bovine serum albumin, was applied to microscopic slides with fixed Mf and then incubated for 2.5 h in humid chambers. The slides were washed in PBS treated with 100-fold-diluted peroxidase-conjugated anti-human IgA (P0216; Dako) in the same buffer. Enzyme reactivity was studied using diaminobenzidine (D5637; Sigma) at a concentration of 0.5 mg/mL in Tris-HCl (pH 8.6) per 1 µL of H<sub>2</sub>O<sub>2</sub>.</p>
<p><bold><italic>Data analysis.</italic></bold> Student's <italic>t</italic> test or the χ<sup>2</sup> test was applied to determine the statistical significance of differences between or within groups, and the relationship between variables was evaluated by Pearson's coefficient of correlation. All statistical tests were performed using GraphPad Prism software (version 4.0). Differences were considered significant at <italic>P</italic><.05.</p>
</sec>
<sec sec-type="results">
<title>Results</title>
<p>Based on the status of microfilaremia, antigenemia, and chronic disease manifestations, the study subjects were classified into 4 categories, as described in Subjects, Materials, and Methods. <xref ref-type="fig" rid="F7">Table 1</xref> shows the number of subjects, sex distribution, median age, Mf status, Mf density, CFA status, and CFA density for the different categories.</p>
<p><bold><italic>Total serum IgA1 levels in the clinical spectrum of human filariasis.</italic></bold> Because IgA1 constitutes 90% of total plasma [<xref ref-type="bibr" rid="R19">19</xref>], the lectin-based solid-phase assay, which quantifies IgA1, was taken as a measure of total IgA in this study. IgA1 levels in Mf carriers were significantly lower than those in the other 3 groups (<xref ref-type="fig" rid="F1">figure 1<italic>A</italic></xref>). The negative correlation observed between the density of filarial infection (CFA levels) and total serum IgA1 levels suggests that the intensity of infection with adult worms could influence total IgA1 levels in human filariasis (<xref ref-type="fig" rid="F1">figure 1<italic>B</italic></xref>). Such an association, however, was not found between Mf density and IgA1 levels (<xref ref-type="fig" rid="F1">figure 1<italic>C</italic></xref>).</p>
<p><bold><italic>Comparison of</italic> B. pahangi <italic>and</italic> S. digitata <italic>antigens for IgA quantification.</italic></bold> Parasite extracts prepared from <italic>B. pahangi</italic> and <italic>S. digitata</italic> were compared for their sensitivity and specificity, because many investigators use extracts of adult <italic>Brugia</italic> organisms for immunological assays. The IgA levels measured using the 2 parasite preparations were comparable (<xref ref-type="fig" rid="F2">figure 2<italic>A</italic></xref>), indicating the applicability of <italic>S. digitata</italic> parasites for immunological studies of human filariasis. This was further substantiated when a panel of serum samples (from 5 clinical groups) was tested against <italic>Sd</italic>-F-Ag and <italic>Bp</italic>-F-Ag, with comparable results; significantly lower levels of IgA were observed in Mf carriers, and, more interestingly, the IgA levels were significantly higher in putatively immune subjects (the endemic controls) than in all other groups. These observations were consistent regardless of the parasite species used in the assays, whether <italic>S. digitata</italic> or <italic>B. pahangi</italic> (figure <xref ref-type="fig" rid="F2">2<italic>B</italic></xref> and <xref ref-type="fig" rid="F2">2<italic>C</italic></xref>). The geometric mean index (GMI) of IgA to <italic>Sd</italic>-F-Ag in Mf carriers was 24.68% of that in endemic controls, whereas the GMI of IgA to <italic>Bp</italic>-F-Ag in asymptomatic carriers was 19.22% of that in endemic controls. Seven outliers were much more reactive to <italic>Brugia</italic> organisms than to <italic>Setaria</italic> organisms (<xref ref-type="fig" rid="F2">figure 2<italic>A</italic></xref>), but these samples did not belong to a particular category.</p>
<p><bold><italic>IgA to</italic> Sd<italic>-F-pro and</italic> Sd<italic>-F-cho in human filariasis.</italic></bold> The observed differences in IgA titers between clinical groups was consistent when purified protein (<italic>Sd</italic>-F-pro) or carbohydrate (<italic>Sd</italic>-F-cho) fractions were used in the immunoassays (figure <xref ref-type="fig" rid="F3">3<italic>A</italic></xref> and <xref ref-type="fig" rid="F3">3<italic>B</italic></xref>), suggesting that filaria-specific IgA antibodies are directed toward both protein and carbohydrate moieties. Crucially, levels of IgA in putatively immune subjects were elevated in comparison with 3 other clinical groups when serum samples were tested with either protein or carbohydrate fractions of parasites (figure <xref ref-type="fig" rid="F3">3<italic>A</italic></xref> and <xref ref-type="fig" rid="F3">3<italic>B</italic></xref>). The GMI of IgA to <italic>Sd</italic>-F-pro in Mf carriers was 41.32% of that in endemic controls, whereas the GMI of IgA antibodies to <italic>Sd</italic>-F-cho in asymptomatic subjects was 54.82% of that in putatively immune subjects.</p>
<p><bold><italic>Association between decreased filaria-specific IgA levels and active infection.</italic></bold> When the serum samples were reclassified according to infection status without regard for presentation of symptoms, subjects with current infection (as shown by the presence of CFA [<xref ref-type="fig" rid="F4">figure 4<italic>A</italic></xref>] and/or Mf [<xref ref-type="fig" rid="F4">figure 4<italic>B</italic></xref>]) were found to have significantly less filaria-specific IgA than subjects who were free of active infection, suggesting that increased levels of IgA could contribute to the absence of active infection.</p>
<p><bold><italic>Influence of sex on levels of filaria-specific IgA.</italic></bold> A significant difference in filaria-specific IgA was observed when IgA levels were analyzed according to sex; the antibody levels were significantly higher in female subjects than in male subjects (<xref ref-type="fig" rid="F4">figure 4<italic>C</italic></xref>). This association was consistent when the samples were classified on the basis of the presence or absence of filarial infection in male and female subjects (<xref ref-type="fig" rid="F4">figure 4<italic>D</italic></xref>).</p>
<p><bold><italic>Age-specific distribution of IgA antibodies.</italic></bold> In filariasis-endemic areas, the population is subjected to continuous exposure to infective larvae, and filaria-specific IgA levels were studied in an age-stratified population. Antibody levels reached their peak by age 20 years and remained stable in older age groups (<xref ref-type="fig" rid="F4">figure 4<italic>F</italic></xref>), suggesting that continued exposure beyond 20 years does not significantly alter filaria-specific IgA responses. All of the serum samples for the age group <20 years were from subjects aged 10–20 years, and there was no significant correlation between age and acquisition of filaria-specific IgA (<xref ref-type="fig" rid="F4">figure 4<italic>E</italic></xref>).</p>
<p><bold><italic>IgA to developmental stages of filarial parasites.</italic></bold> The above-described investigations were performed with antigen extracts prepared from adult female-stage parasites (<italic>Sd</italic>-F-Ag). Because the antibody levels were significantly higher in putatively immune subjects, it was of interest to study levels of IgA to other developmental stages to which the human immune system is exposed during natural infection. The following preparations were tested: (1) adult male-stage parasites of <italic>S. digitata</italic> (<italic>Sd</italic>-M-Ag), (2) intrauterine stages of adult female parasites of <italic>S. digitata</italic> (<italic>Sd</italic>-IUS-Ag), (3) excretory-secretory antigens of adult female worms of <italic>S. digitata</italic> (<italic>Sd</italic>-F-ES-Ag), and (4) infective larval (L3) extract of <italic>B. pahangi</italic> (<italic>Bp</italic>-L3-Ag). Detailed results are shown in <xref ref-type="fig" rid="F5">figure 5</xref>. First, profiles of filaria-specific IgA to male worms (<italic>Sd</italic>-M-Ag) were very similar to those observed earlier for IgA to female worms (<italic>Sd</italic>-F-Ag); that is, putatively immune subjects displayed significantly higher levels than did subjects in other categories (<xref ref-type="fig" rid="F5">figure 5<italic>A</italic></xref>). Second, levels of IgA to <italic>Sd</italic>-IUS-Ag were comparable in all the clinical groups (<xref ref-type="fig" rid="F5">figure 5<italic>B</italic></xref>). Because intrauterine stages are constitutively part of adult female worms, the results shown in figures <xref ref-type="fig" rid="F2">2<italic>B</italic></xref> and <xref ref-type="fig" rid="F5">5<italic>B</italic></xref> suggest that protective IgA to adult worms are directed toward filarial antigens other than those present in intrauterine embryogenic stages in female worms. On the other hand, levels of IgA to <italic>Sd</italic>-F-ES-Ag were significantly higher in infection-free individuals (endemic controls and subjects with chronic disease) than in infected subjects (asymptomatic subjects and those with cryptic infection) (<xref ref-type="fig" rid="F5">figure 5<italic>C</italic></xref>).</p>
<p>The presence of similar antigenic epitopes in <italic>Sd</italic>-F-Ag and <italic>Bp</italic>-F-Ag prompted us to study IgA to larval extract of <italic>B. pahangi</italic> (<italic>Bp</italic>-L3-Ag) in different clinical categories. The levels were significantly higher in subjects with chronic disease than in endemic controls and Mf carriers. IgA levels were also significantly higher in subjects with cryptic infections than in Mf carriers (<xref ref-type="fig" rid="F5">figure 5<italic>D</italic></xref>).</p>
<p>All of the solid-phase immunoassays described above were performed by using soluble products or solubilized extracts of the parasites. Reactivity in such assays does not indicate the anatomical location of the epitopes in parasites reacting to filaria-specific IgA. Because the surfaces of adult-stage pathogenic systemic nematodes are constantly exposed to the host immune system, an immunoperoxidase assay was performed using cross-sections of adult female worms of <italic>S. digitata</italic> to score for reactivity of filaria-specific IgA to the surface (epicuticle or cuticle) (<italic>Sd</italic>-F-S) of parasites in different clinical groups; the results are shown in <xref ref-type="fig" rid="F6">figure 6</xref>. IgA antibodies to <italic>Sd</italic>-F-S were demonstrated in 80% of endemic controls, 48% of subjects with chronic disease, and 48% of Mf carriers (<xref ref-type="fig" rid="F6">figure 6<italic>C</italic></xref>).</p>
</sec>
<sec sec-type="discussion">
<title>Discussion</title>
<p>The existence of acquired protective immunity in lymphatic filariasis has been a subject of intense debate [<xref ref-type="bibr" rid="R3">3</xref>]. The antigen-detection assays for bancroftian filariasis that we used in the present study have allowed us to identify infected subjects precisely, addressing the issue of protective immunity. Generally, the absence of infection or a low infection load is considered a parameter of protective immunity in experimental filariasis (as in many other models of pathogens) [<xref ref-type="bibr" rid="R14">14</xref>, <xref ref-type="bibr" rid="R20">20</xref>, <xref ref-type="bibr" rid="R21">21</xref>]. In human filariasis, however, genuine protective immunity should be a state associated with the absence of infection as well as disease because a large proportion of infected subjects are free of clinical disease and most patients with acute or chronic disease are free of demonstrable current infection [<xref ref-type="bibr" rid="R3">3</xref>]. Because endemic controls are free of demonstrable infection as well as disease, we and others have considered this group to represent putatively immune individuals in filariasis-endemic areas [<xref ref-type="bibr" rid="R3">3</xref>, <xref ref-type="bibr" rid="R22">22</xref>–<xref ref-type="bibr" rid="R24">24</xref>]. Several studies have been conducted of IgG (isotypes IgG1, IgG2, IgG3, and IgG4), IgM, and IgE antibody responses to different filarial antigens in the context of protective immunity in human and experimental filariasis [<xref ref-type="bibr" rid="R25">25</xref>–<xref ref-type="bibr" rid="R27">27</xref>]. Although serum IgA constitutes nearly 15%–20% of the total immunoglobulins in humans [<xref ref-type="bibr" rid="R28">28</xref>], there has been no attempt to date to investigate the role played by the IgA antibody response in the clinical spectrum of bancroftian filariasis, and the present study is an attempt to fill this lacuna.</p>
<p>Access to male and female adult <italic>S. digitata</italic> worms free of host tissue or cells, intrauterine embryogenic stages, and excretory-secretory antigens of this parasite offered opportunities to investigate the role played by filaria-specific IgA in bancroftian filariasis. The utility of <italic>S. digitata</italic> for immunological, chemotherapeutic, and other biological studies has been shown by us and others [<xref ref-type="bibr" rid="R29">29</xref>–<xref ref-type="bibr" rid="R31">31</xref>]. The current investigations have revealed several hitherto unknown aspects of the immunology of human filariasis. Subjects with circulating Mf were not only deficient in filaria-specific IgA, compared with other clinical groups, but they also had significantly lower levels of total serum IgA1. IgA deficiency in mice has been reported to be associated with decreased Th1 responses, characterized by low interferon-γ production by T cells [<xref ref-type="bibr" rid="R32">32</xref>]. Humans with microfilaremia display a phenotype characteristic of lower Th1 responses [<xref ref-type="bibr" rid="R33">33</xref>], and our observation of decreased levels of IgA fits into this paradigm. We had expected, however, that this could have been compensated for by dominant Th3/Tr1-type filaria-specific responses (associated with increased production of transforming growth factor-β and/or interleukin-10), which are observed in helminth infections in general [<xref ref-type="bibr" rid="R34">34</xref>] and filariasis in particular [<xref ref-type="bibr" rid="R35">35</xref>, <xref ref-type="bibr" rid="R36">36</xref>]. Such compensatory responses do not seem to be operational, because Mf-infected subjects displayed significantly lower total and filaria-specific serum IgA levels. Recently, it has been reported that inducible nitric oxide synthase (iNOS) could very significantly influence a class switch from µ-chain to α-chain [<xref ref-type="bibr" rid="R37">37</xref>], and our observation of decreased IgA levels could be related to the status of iNOS induction in the Mf-infected subjects. Although a role for nitric oxide in the experimental murine filariasis model has been reported by us and others [<xref ref-type="bibr" rid="R38">38</xref>–<xref ref-type="bibr" rid="R40">40</xref>], it is not clear whether such a scenario is responsible for the low IgA levels in Mf carriers that we observed in this study.</p>
<p>Regardless of the factors that influence the production of IgA during the immune response, this study has indicated a protective role for IgA in human filariasis. We have adopted a rigorous and robust definition of protective immunity, because infection and disease often do not coexist in human filariasis [<xref ref-type="bibr" rid="R41">41</xref>, <xref ref-type="bibr" rid="R42">42</xref>]. Filaria-specific IgA levels were significantly higher in endemic controls than in subjects with chronic disease, suggesting a role for IgA in antidisease immunity. Furthermore, higher IgA levels were significantly correlated with the absence of filarial infection (figure <xref ref-type="fig" rid="F4">4<italic>A</italic></xref> and <xref ref-type="fig" rid="F4">4<italic>B</italic></xref>). Such associations were consistently observed when levels of IgA to extracts of both male- and female-stage parasites were analyzed. The present investigation has also revealed differential IgA levels for different developmental stages, surface versus excretory products, and protein versus carbohydrate components of parasites.</p>
<p>Immune responses to filarial antigens are differentially influenced by sex; males are genetically predisposed to have lower production of IgE than females, causing enhanced pathology [<xref ref-type="bibr" rid="R43">43</xref>]. Increased susceptibility in males has also been reported in animal models of filariasis [<xref ref-type="bibr" rid="R44">44</xref>, <xref ref-type="bibr" rid="R45">45</xref>]. Consistent with these findings, in the present study we found significantly lower levels of filaria-specific IgA in male subjects than in female subjects, which presumably could be responsible for the epidemiological observations of an increased prevalence of filariasis in males; none of the other immunological parameters reported in the literature account for sex-related differences in the susceptibility to filarial infection in human communities. Ongoing studies in our laboratory are now directed toward identification of molecules or epitopes that are recognized by protective filarial IgA in human filariasis. Mouse strains deficient in secretory IgM have been used recently to demonstrate their role in antilarval immunity in experimental models of filariasis [<xref ref-type="bibr" rid="R46">46</xref>]. Similar investigations using IgA-deficient mice [<xref ref-type="bibr" rid="R47">47</xref>] can be expected to throw further light on the precise role played by IgA antibodies in filarial immunology.</p>
</sec>
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<title>Figures and Tables</title>
<fig id="F1" position="float">
<label>Figure 1</label>
<caption>
<p><italic>A</italic>, Total IgA ELISA. Microfilariae (Mf) carriers had significantly lower levels of total serum IgA1 than did other groups. Shown are results for asymptomatic Mf carriers (AS; <italic>n</italic>=38); subjects with chronic filarial disease, namely, lymphedema or elephantiasis (CH; <italic>n</italic>=40); subjects with cryptic infection (i.e., asymptomatic amicrofilaremic subjects with active infection) (CR; <italic>n</italic>=39); and endemic controls (putatively immune subjects from areas of endemicity) (EC; <italic>n</italic>=40). <italic>B</italic>, Negative correlation between filarial infection (circulating filarial antigen [CFA]) density and total serum IgA1 levels (<italic>r</italic>=−0.248; <italic>P</italic>=.0326) in serum samples from 74 subjects in the AS and CR groups. <italic>C</italic>, Absence of a relationship between Mf density and total serum IgA1 in serum samples from the AS group (<italic>n</italic>=35).</p>
</caption>
<graphic mimetype="image" xlink:href="198-3-434-fig001.tif"></graphic>
</fig>
<fig id="F2" position="float">
<label>Figure 2</label>
<caption>
<p><italic>A</italic>, Correlation between filaria-specific IgA antibodies to <italic>Bp-</italic>F-Ag and <italic>Sd</italic>-F-Ag by ELISA in serum samples from subjects with 4 different clinical categories of human filariasis (<italic>n</italic>=78). A significant positive correlation was observed between antigens prepared from 2 filarial parasites (r=0.509; <italic>P</italic><.0001). <italic>B</italic>, Significantly higher levels of IgA to <italic>Sd</italic>-F-Ag in endemic controls (EC; putatively immune subjects from areas of endemicity) than in subjects in other categories (<italic>t</italic> test). For nonendemic controls (NEC; control subjects from filaria-nonendemic areas) vs. subjects with chronic disease (CH), <italic>P</italic>=.0456; for NEC vs. subjects with cryptic infection (CR), <italic>P</italic>=.0325; for NEC vs. EC, <italic>P</italic><.0001; for CH vs. EC, <italic>P</italic>=.0001; for CR vs. EC, <italic>P</italic><.0001; for asymptomatic microfilariae carriers (AS) vs. EC, <italic>P</italic><.0001; for CR vs. AS, <italic>P</italic>=.0026; for CH vs. AS, <italic>P</italic>=0.0132 (<italic>n</italic>=14 for NEC; <italic>n</italic>=20 for other categories). <italic>C</italic>, Significant elevation of filaria-specific (<italic>Bp</italic>-F-Ag) IgA levels in the EC group compared with the other categories of human bancroftian filariasis (<italic>t</italic> test). For NEC vs. CH, <italic>P</italic>=.0127; for NEC vs. CR, <italic>P</italic>=.0003; for NEC vs. EC, <italic>P</italic><.0001; for CH vs. EC, <italic>P</italic>=.0062; for CR vs. EC, <italic>P</italic>=.0043; for AS vs. EC, <italic>P</italic><.0001; for CR vs. AS, <italic>P</italic>=.0009; for CH vs. AS, <italic>P</italic>=.0129.</p>
</caption>
<graphic mimetype="image" xlink:href="198-3-434-fig002.tif"></graphic>
</fig>
<fig id="F3" position="float">
<label>Figure 3</label>
<caption>
<p><italic>A</italic>, Levels of IgA to <italic>Sd</italic>-F-pro across the clinical spectrum of filarial disease: endemic controls (putatively immune subjects from areas of endemicity) (EC; <italic>n</italic>=21), subjects with chronic disease (CH; <italic>n</italic>=36), asymptomatic microfilariae carriers (AS; <italic>n</italic>=13), and subjects with cryptic infection (CR; <italic>n</italic>=16). Subjects in the EC group had significantly higher levels of IgA than did subjects in the other 3 groups. <italic>B</italic>, Levels of IgA to <italic>Sd</italic>-F-cho across the clinical spectrum: EC (<italic>n</italic>=14), CH (<italic>n</italic>=32), AS (<italic>n</italic>=13), and CR (<italic>n</italic>=12). IgA levels were significantly higher in the EC group than in the other 3 groups.</p>
</caption>
<graphic mimetype="image" xlink:href="198-3-434-fig003.tif"></graphic>
</fig>
<fig id="F4" position="float">
<label>Figure 4</label>
<caption>
<p><italic>A</italic>, Association between filaria-specific IgA levels and infection status. Levels of IgA to <italic>Sd</italic>-F-Ag were significantly higher in subjects without demonstrable filarial infections than in those with circulating filarial antigen (CFA). Serum samples from CFA-positive (asymptomatic microfilariae [Mf] carriers [AS] plus subjects with cryptic infection [CR]; <italic>n</italic>=85) or CFA-negative subjects (endemic controls [EC; putatively immune subjects from areas of endemicity] plus subjects with chronic filarial disease [CH]; <italic>n</italic>=90) were tested for IgA (1 subject from the CH group displayed active filarial infection). <italic>B</italic>, Significantly higher levels of IgA antibodies to <italic>Sd</italic>-F-Ag in amicrofilaremic subjects than in microfilaremic individuals. Serum samples from Mf-positive (AS; <italic>n</italic>=42) or Mf-negative (EC plus CH plus CR; <italic>n</italic> = 133) subjects were tested for IgA. <italic>C</italic>, Association between sex and filaria-specific IgA levels. Serum samples from 120 male and 53 female subjects were tested for IgA to <italic>Sd-</italic>F-Ag. Female subjects had significantly higher levels of IgA than did male subjects (<italic>t</italic> test). <italic>D</italic>, Association between sex and filaria-specific IgA in 2 clinical groups. Male and female subjects in the CFA-positive (57 male and 28 female subjects) and CFA-negative (32 male and 21 female subjects) categories were tested for IgA levels (<italic>t</italic> test). <italic>E</italic>, Relationship between filaria-specific IgA antibodies and years of exposure (10–20 years) to filarial parasites, as shown by ages of residents in areas of endemicity. <italic>F</italic>, Prevalence of filaria-specific IgA antibodies in subjects with bancroftian filariasis, stratified by age. No significant difference was observed among the groups.</p>
</caption>
<graphic mimetype="image" xlink:href="198-3-434-fig004.tif"></graphic>
</fig>
<fig id="F5" position="float">
<label>Figure 5</label>
<caption>
<p><italic>A</italic>, ELISA results showing significant elevation of filaria-specific IgA antibodies to male worm extracts (<italic>Sd</italic>-M-Ag) in endemic controls (EC; putatively immune subjects from areas of endemicity) in comparison with other categories of human bancroftian filariasis (<italic>t</italic> test). For nonendemic controls (NEC; control subjects from filaria-nonendemic areas) vs. subjects with chronic filarial disease (CH), <italic>P</italic>=.0425; for NEC vs. EC, <italic>P</italic><.0001; for CH vs. EC, <italic>P</italic>=.0237; for subjects with cryptic infection (CR) vs. EC, <italic>P</italic><.0001, for asymptomatic microfilariae carriers (AS) vs. EC, <italic>P</italic>=.0002 (<italic>n</italic>=14 for NEC; <italic>n</italic>=20 for other categories). <italic>B</italic>, No significant difference in IgA levels among the 4 categories when tested against <italic>Sd</italic>-IUS-Ag (<italic>t</italic> test; <italic>n</italic>=20 subjects in each category). <italic>C</italic>, IgA to <italic>Sd</italic>-F-ES-Ag across the clinical spectrum of human filariasis (<italic>t</italic> test; <italic>n</italic>=20 subjects in each category). <italic>D</italic>, Levels of IgA to <italic>Bp</italic>-L3-Ag in different clinical categories of human bancroftian filariasis (<italic>t</italic> test; <italic>n</italic>=20 subjects in each category).</p>
</caption>
<graphic mimetype="image" xlink:href="198-3-434-fig005.tif"></graphic>
</fig>
<fig id="F6" position="float">
<label>Figure 6</label>
<caption>
<p>IgA to cuticles <italic>(arrow in A and B)</italic> of adult-stage parasites. Adult female <italic>Setaria digitata</italic> worms fixed in 4% paraformaldehyde were used to prepare 5-µm-thick cross-sections by microtomy, and immunoperoxidase assay was performed. <italic>A</italic>, Conjugate control. <italic>B</italic>, Binding of IgA to surfaces of adult worms. <italic>C</italic>, IgA antibodies to <italic>Sd</italic>-F-S (epicuticle or cuticle). The mean percentage of endemic controls (EC; putatively immune subjects from areas of endemicity) displaying IgA antibodies to <italic>Sd</italic>-F-S (epicuticle or cuticle) was significantly higher than that in subjects with chronic filarial (CH) disease and asymptomatic microfilariae carriers (AS) (<italic>n</italic>=15 in each group)</p>
</caption>
<graphic mimetype="image" xlink:href="198-3-434-fig006.tif"></graphic>
</fig>
<fig id="F7" position="float">
<label>Table 1</label>
<caption>
<p>Details of the study population in different areas of Orissa endemic for bancroftian filariasis.</p>
</caption>
<graphic mimetype="image" xlink:href="198-3-434-tbl001.tif"></graphic>
</fig>
</sec>
<fn-group>
<fn fn-type="other">
<p>Potential conflicts of interest: none reported.</p>
</fn>
<fn fn-type="financial-disclosure">
<p>Financial support: Indian Council of Medical Research (grants to the Regional Medical Research Centre); Department of Biotechnology, Ministry of Science and Technology, government of India (grants to the Institute of Life Sciences); European Union (grant IC-18-CT 97–0245 to B.R.).</p></fn>
</fn-group>
</back>
</article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Protective Immunity in Human Filariasis: A Role for Parasite-Specific IgA Responses</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Protective Immunity in Human Filariasis: A Role for Parasite-Specific IgA Responses</title></titleInfo><name type="personal"><namePart type="given">Bikash R.</namePart><namePart type="family">Sahu</namePart><affiliation>Regional Medical Research Centre, Bhubaneswar, India</affiliation><description>a Present affiliations: Institute of Life Sciences, Bhubaneswar (B.R.S.), and Enterovirus Research Centre, Mumbai (M.C.M.), India.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Madhu C.</namePart><namePart type="family">Mohanty</namePart><affiliation>Regional Medical Research Centre, Bhubaneswar, India</affiliation><description>a Present affiliations: Institute of Life Sciences, Bhubaneswar (B.R.S.), and Enterovirus Research Centre, Mumbai (M.C.M.), India.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Prakash K.</namePart><namePart type="family">Sahoo</namePart><affiliation>Regional Medical Research Centre, Bhubaneswar, India</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ashok K.</namePart><namePart type="family">Satapathy</namePart><affiliation>Regional Medical Research Centre, Bhubaneswar, India</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal" displayLabel="corresp"><namePart type="given">Balachandran</namePart><namePart type="family">Ravindran</namePart><affiliation>Regional Medical Research Centre, Bhubaneswar, India</affiliation><affiliation>Institute of Life Sciences, Bhubaneswar, India</affiliation><affiliation>E-mail: ravindran8@gmail.com</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><originInfo><publisher>The University of Chicago Press</publisher><dateIssued encoding="w3cdtf">2008-08-01</dateIssued><copyrightDate encoding="w3cdtf">2008</copyrightDate></originInfo><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract>Background. Filaria-specific antibodies of immunoglobulin (Ig) G, IgE, and IgM isotypes have been correlated with acquired immunity in the literature, but the status of filaria-specific IgA and its role in human filariasis has not been addressed. The present study attempts to fill this lacuna. Methods. Both total and filaria-specific IgA to different developmental stages of filarial parasites were quantified by solid-phase immunoassays in 412 clinically and parasitologically defined cases occurring in an area endemic for human bancroftian filariasis in Orissa, India. Results. Compared with other clinical categories, microfilariae carriers were deficient in total as well as filaria-specific IgA. More crucially, significantly high levels were observed in putatively immune control subjects from areas of endemicity. These associations were also related to sex; female subjects in each category displayed higher levels of filaria-specific IgA than did male subjects. Conclusion. The study demonstrates, for the first time, a positive correlation between protective immunity and increased levels of filaria-specific IgA in human bancroftian filariasis. Furthermore, filaria-specific IgA appears to be an immunological window for the sex-related differences in susceptibility to infection observed in human filariasis.</abstract><note type="footnotes">Present affiliations: Institute of Life Sciences, Bhubaneswar (B.R.S.), and Enterovirus Research Centre, Mumbai (M.C.M.), India.</note><relatedItem type="host"><titleInfo><title>The Journal of Infectious Diseases</title></titleInfo><titleInfo type="abbreviated"><title>The Journal of Infectious Diseases</title></titleInfo><genre type="journal">journal</genre><identifier type="ISSN">0022-1899</identifier><identifier type="eISSN">1537-6613</identifier><identifier type="PublisherID">jid</identifier><identifier type="PublisherID-hwp">jinfdis</identifier><part><date>2008</date><detail type="volume"><caption>vol.</caption><number>198</number></detail><detail type="issue"><caption>no.</caption><number>3</number></detail><extent unit="pages"><start>434</start><end>443</end></extent></part></relatedItem><identifier type="istex">09A1CB0FBA6BC188AF0B11AB4C16287E69942032</identifier><identifier type="DOI">10.1086/589881</identifier><accessCondition type="use and reproduction" contentType="copyright">© 2008 by the Infectious Diseases Society of America</accessCondition><recordInfo><recordContentSource>OUP</recordContentSource></recordInfo></mods></metadata><covers><json:item><extension>tiff</extension><original>true</original><mimetype>image/tiff</mimetype><uri>https://api.istex.fr/document/09A1CB0FBA6BC188AF0B11AB4C16287E69942032/covers/tiff</uri></json:item><json:item><extension>html</extension><original>true</original><mimetype>text/html</mimetype><uri>https://api.istex.fr/document/09A1CB0FBA6BC188AF0B11AB4C16287E69942032/covers/html</uri></json:item></covers><annexes><json:item><extension>jpeg</extension><original>true</original><mimetype>image/jpeg</mimetype><uri>https://api.istex.fr/document/09A1CB0FBA6BC188AF0B11AB4C16287E69942032/annexes/jpeg</uri></json:item><json:item><extension>gif</extension><original>true</original><mimetype>image/gif</mimetype><uri>https://api.istex.fr/document/09A1CB0FBA6BC188AF0B11AB4C16287E69942032/annexes/gif</uri></json:item><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/document/09A1CB0FBA6BC188AF0B11AB4C16287E69942032/annexes/pdf</uri></json:item></annexes><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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